IDENTIFICATION OF CYTOCHROME P4503A AS THE MAJOR ENZYME SUBFAMILY RESPONSIBLE FOR THE METABOLISM OF -DIHYDRO-13-O-[(2-METHOXYETHOXY)METHYL]-AVERMECTIN B-1 AGLYCONE BY RAT-LIVER MICROSOMES

1. Metabolism of -dihydro-13-O-[(2-methoxyethoxy)methyl]-avermectin B- 1 aglycone (MEM-H2B2), a new avermectin, by rat liver microsomes has b een studied. Metabolites identified were formed by demethylation of th e methoxyethoxymethoxy (MEM) side chain, loss of the MEM side chain, p artial cleavage and further oxidation of che MEM side chain, and oxida tion of the aglycone after cleavage of the MEM side chain. 2. The spec ific cytochrome P450 isoforms involved in the metabolism of MEM-H2B1 w ere identified through immunoinhibition studies. Among several antibod ies prepared against various cytochrome P450s, only anti-rat P4503A Ig G inhibited MEM-H2B1 metabolism by liver microsomes from the untreated rat. Moreover, troleandomycin, a selective suicide inhibitor for enzy mes of the cytochrome P4503A family, inhibited the total metabolism by > 80 %,. These results clearly indicate that cytochrome P4503A is pri marily responsible for the metabolism of MEM-H2B1. 3. Secondary metabo lism was evident in the metabolism of MEM-H2B1 by dexamethasone and ph enobarbital induced liver microsomes, where different isoform(s) of cy tochrome P4503A could be involved in these multiple step reactions.